Diverse roles of the Bone Morphogenetic Proteins in the developing spinal cord

骨形态发生蛋白在脊髓发育中的多种作用

基本信息

批准号：
9269370
负责人：
SAMANTHA J BUTLER
金额：
$ 4.21万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269370
关键词：
Address Axon BMP4 BMP5 gene BMP6 gene BMP7 gene Biological Assay Bone Morphogenetic Proteins Cell physiology Cells ChIP-seq Chickens Complex Development Disease Dorsal Electroporation Embryo Extracellular Domain Growth Health In Vitro Individual Injury Interneurons Light Mediating Modeling Mus Neurons Organism Output Pathway interactions Pattern Phosphotransferases Population Process Receptor Activation Regulation Role Second Messenger Systems Signal Pathway Signal Transduction Specificity Spinal Spinal Cord Spinal cord damage Time Tissues To specify Translating axon guidance base bone morphogenetic protein receptor type I cell fate specification cofilin embryonic stem cell growth differentiation factor 7 in vivo member morphogens nerve stem cell neural circuit receptor relating to nervous system second messenger tissue culture

项目摘要

DESCRIPTION (provided by applicant): Inductive growth factors are used reiteratively throughout development to direct an extraordinary range of cellular fates and processes. This economy of signaling means that complex organisms can be generated by a relatively small number of signals, but it requires developing cells to differentially interpret the activities of growth factors over time. We have been studying the mechanisms by which the Bone Morphogenetic Proteins (BMPs) are used reiteratively to establish dorsal circuitry in the developing spinal cord. These studies will shed direct light both on our ability to rebuild the spinal cord after injury and our understanding of the congenital diseases that result from deficits in the BMP signaling pathway. The BMPs act from the roof plate (RP) to first pattern the surrounding tissue and then provide guidance information to axons extending away from the dorsal midline. Surprisingly, the mode by which the BMPs induce cell fate remains unclear: although it is widely assumed that they act as morphogens to pattern the dorsal spinal cord, this model has not been clearly demonstrated. Rather, there are many BMPs present in the RP and our preliminary studies suggest that they have distinct effects on the induction of particular neural fates. We will resolve whether the BMPs act quantitatively as morphogens or more qualitatively to specify cell fate in Aim 1. In Aim 2, we will determine how the distinct activitie of the BMPs are translated by dorsal interneurons (INs) to result in different cellular fates and/or processes. Our previous studies have suggested that dorsal INs interpret the distinct activities of the BMPs at both the receptor and second messenger level. A redundant activity common to both type I BMP receptors, BmprIa and BmprIb, permits them to mediate the specification of dorsal cell fates by activating the canonical Smad intermediate, Smad5. In contrast, BmprIb uniquely mediates the guidance activities of the BMPs, by activating the Lim kinase 1 (Limk1)/cofilin pathway and (putatively) Smad1. We will assess both the mechanistic basis by which Smad1, Smad5 and Limk1 are differentially activated by the type I Bmprs and the different mechanisms by which Smad5 and Smad1 then differentially respectively regulate cell fate specification and the control of axon extension in the following aims: Aim 1: Determine the mode by which multiple BMPs direct cell fate in the dorsal spinal cord. Hypothesis: Distinct BMPs qualitatively differentiate progenitor neurons into distinct dorsal IN populations. Aim 2: Determine the mechanism(s) by which dorsal spinal neurons translate the differential activities of the BMPs. Hypothesis: The distinct activities of the BMPs in the dorsal spinal cord are translated by distinct patterns of receptor activation and/or the action of specific second messengers.

描述（由申请人提供）：诱导生长因子在整个发育过程中反复使用，以指导一系列非凡的细胞命运和过程。这种信号经济意味着复杂的生物体可以通过相对少量的信号产生，但它需要发育中的细胞。我们一直在研究重复使用骨形态发生蛋白 (BMP) 在脊髓中建立背侧回路的机制。阐明我们在受伤后重建脊髓的能力以及我们对缺陷导致的先天性疾病的理解 BMP 信号通路从顶板 (RP) 开始作用，首先对周围组织进行模式化，然后向远离背中线的轴突提供指导信息，但 BMP 诱导细胞命运的模式仍不清楚：尽管人们普遍认为它们作为形态发生素来形成背侧脊髓，但这种模型尚未得到明确证明，相反，RP 中存在许多 BMP，我们的初步研究表明它们对背侧脊髓具有明显的影响。在目标 1 中，我们将解决 BMP 是定量地充当形态发生剂还是更定性地指定细胞命运。在目标 2 中，我们将确定背侧中间神经元 (IN) 如何翻译 BMP 的独特活动。我们之前的研究表明，背侧 IN 在受体和第二信使水平上解释了 BMP 的不同活性。 I 型 BMP 受体 BmprIa 和 BmprIb 共有，允许它们通过激活经典的 Smad 中间体 Smad5 介导背侧细胞命运的规范，相反，BmprIb 通过激活 Lim 激酶 1 独特地介导 BMP 的引导活性。 (Limk1)/cofilin 途径和（推定）Smad1 我们将评估其机制基础。 Smad1、Smad5 和 Limk1 被 I 型 Bmprs 差异激活，并且通过不同的机制，Smad5 和 Smad1 分别差异调节细胞命运规范和轴突延伸控制，目的如下：目标 1：确定多个 BMP 的模式假设：不同的 BMP 将祖神经元定性地分化为不同的背侧 IN 群体。背脊髓神经元翻译 BMP 不同活性的机制假设：背脊髓中 BMP 的不同活性是通过不同的受体激活模式和/或特定第二信使的作用来翻译的。